The Importance Of Sulfation In Thyroid Hormone Metabolism

The role of sulfation in thyroid hormone metabolism is intriguing. Sulfated iodo-thyronines do not bind to the thyroid hormone receptors nor are they substrates for D2 and D3, but their deiodination by D1 is strongly augmented. Figure 7.2 shows the effects of sulfation on the deiodination of different iodothyronines by D1 (Visser, 1996b). IRD (inactivation) of T4 sulfate (T4S) and T3 sulfate (T3S) is markedly facilitated, whereas outer ring deiodination (activation) of T4S is blocked (Visser,...

Ontogeny And Tissue Distribution Of Iodothyronine Sulfotransferases

The expression of the different sulfotransferases is tissue- and developmental stage-dependent. Richard et al. (2001) studied the ontogeny of SULT1A1 and 1A3 in human tissues. They found high but variable hSULT1A1 expression in the fetal and postnatal human liver, which reached half the expression level of adult liver. hSULT1A3 is differently regulated highest hSULT1A3 expression in the liver was found early in development, decreasing in the late fetal and early neonatal period, being absent in...

Sulfotransferase Expression And Its Control In Breast Cancer

SULT1E1 is the only sulfotransferase that displays affinity for 17p estradiol in a physiological (nanomolar) concentration range (Zhang et al., 1998). Other SULTs, including SULT1A1 and SULT1A3, are able to sulfate estrogens in vitro however. For example, cells transfected with the cDNA coding for the enzyme originally called placental hEST 1 (Bernier et al., 1994b Luu-The et al., 1996), now identified as SULT1A3, was able to transform estrone to EjS at nanomolar concentrations (Bernier et al.,...

Interindividual Variability In The Sulfation Rate Of Drugs In Human Adult Liver And Duodenum

Ten years of activity of this laboratory has shown that the rate of drug sulfation varies in human liver, and variation between the 5th and the 95th percentiles ranged from three to eightfold with different drugs. Several factors, such as environmental factors and genetic factors, contribute to such variation. Descriptive Statistical Analysis of Ritodrine Sulfation Rate and SULT1A3 and SULT1A1 Activities in Mid-Gestation Human Fetal Liver a The variation was calculated by dividing the 95th...

Multiplicity Of Human Sult Activities And Purification Studies

Initial studies of the heterogeneity of the human SULTs focused on two types of SULT activity, the high levels of hydroxysteroid sulfation in the human adrenal gland and multiple forms of phenol SULT activity in human platelets. The human adrenal is responsible for the high levels of dehydroepiandrosterone (DHEA) sulfate present in human fetal plasma. Micromolar concentrations of DHEA-sulfate in adult plasma are due to the synthesis and sulfation of DHEA in the reticular layer of the adrenal...

Sultdependent Activation And Inactivation Chemical Background

SULTs transfer the sulfo sulfuryl group from the cofactor 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to nucleophilic groups of their substrates (Glatt, 2002). The resulting sulfate, thiosulfate, and sulfamate groups are electron-withdrawing and are therefore good leaving groups in certain chemical linkages. A trivial example is H2SO4, which is a strong bivalent acid. Likewise, the sulfate group is readily cleaved off spontaneously in sulfuric acid esters of many benzylic alcohols, allylic...

Hypothetical Correlation Of Proliferation Of The Breast Cancer Cell And Sult Activity

Maximal epithelial mitosis of the normal breast cell is found between 22 and 26 days of the cycle, which corresponds to the high levels of estradiol and progesterone (Longacre and Bartow, 1986). During pregnancy, it is suggested that the elevated values of circulating progesterone are responsible for the induction of lobular-alve-olar development, to prepare the breast for lactation (Russo and Russo, 2002 Topper and Freeman, 1980). The data on the effect of progesterone on breast epithelial...

Sult1

A comparative study of SULT expression in human fetal and adult tissues (notably, liver, lung, kidney, adrenal gland, and intestine) was one of the first to demonstrate the expression of substantial SULT in the fetus (Pacifici et al., 1988). The catecholamine-metabolizing SULT enzyme SULT1A3 is expressed at high levels in fetal liver, in contrast to the adult liver, and the gastrointestinal tract is the major site of expression (Cappiello et al., 1991 Pacifici et al., 1993 Richard et al.,...

Sultdependent Activation Of Carcinogens Historical Background

It is worth mentioning that a sulfuric acid ester, rather than a phase-I metabolite, was the first electrophilic metabolite of a carcinogen to be discovered. This compound was 2-acetylaminofluorene -sulfate (DeBaun et al., 1968 King and Phillips, 1968). Later it was shown that the SULT inhibitor pentachlorophenol drastically decreases the formation of DNA adducts and the induction of tumors by 2-acetyl-aminofluorene and N-hydroxy-2-acetylaminofluorene (29) in rats and mice (Lai et al., 1985,...

F

Falany, Charles, 283 Fenamates, SULT inhibition, 168 Fenoldopam, 158, 165 Fetus development and thyroid hormone, 109-110 drug sulfation in, 159-160 serum iodothyronine sulfate, 124, 129, 130 SULT1A1 activity, 207-208 SULT1A3 activity, 207-208 First exons, untranslated, 8 Flavanoids and breast cancer, 145 SULTs inhibition, 170-171 SULT7A1 sulfation, 15 SULT201 sulfation, 16 Flavones, 171, 172 Flavonol, chimeric constructs, 200 Flufenamic acid, 168 Food additives, 170 Food colorants, 170...

Conclusion On Thyroid Hormone

Species differences of sulfation among experimental animals have been thought to depend on both the kinetic properties and distinct expression profiles in tissues. However, recent gene analyses of humans and experimental animals have indicated that the species difference also depends on the occurrence of the specific gene destruction during animal evolution. More than 50 cDNAs of cytosol sulfotransferase have been isolated from vertebrates at present. In the Genbank database, a number of...

Inhibition Of Sulfotransferase

DCNP was introduced by Mulder and Scholtens (1977) as a selective inhibitor of rat liver SULT1A1 activity. This compound was found to be a better inhibitor of SULT1A1 activity than SULT1A3 activity. Differential inhibition of DCNP was confirmed in human frontal cortex, jejunum, and platelets (Rein et al., 1982). Consistent results have been obtained in human frontal cortex (Rein et al., 1984 Young et al., 1984), FIGURE 9.4 Probit plots of (-)-salbutamol, ritodrine, and minoxidil sulfation rates...

Table of Contents

Nomenclature and Molecular Biology of the Human Sulfotransferase Family 1 Structure and Function of Jyrki Taskinen and Michael W.H. Coughtrie PAPS and Sulfate Conjugation Pharmacogenetics and Richard M. Weinshilboum and Araba A. Adjei Molecular Cloning of the Human Cytosolic Charles N. Falany, Connie A. Meloche, Dongning He, and Josie L. Falany Sulfotransferases in the Human Fetus and Emma L. Stanley, Robert Hume, and Michael W.H. Coughtrie Sulfation of Thyroid Monique H.A. Kester, Michael W.H....

Tissue Distribution Of The Human Sult1a Subfamily

A number of studies have employed metabolic probes and immunohistochemistry techniques to show that SULT1A SULTs exhibit a wide tissue distribution, including liver, lung, brain, skin, platelets, gastrointestinal tissues, and kidney Cappiello et al., 1990 Heroux et al., 1989 Hume and Coughtrie, 1994 Kudlacek et al., 1995 Zou et al., 1990 . However, it was not until 1995, when SULT1A2 was first cloned Ozawa et al., 1995 , that we definitively knew the SULT1A subfamily contained three members,...

Sult2a1

The lack of substrate specificity obscures the biologic roles of SULT2A1, which in humans is primarily expressed in the liver, gastrointestinal tract, and adrenal cortex. Taken together these characteristics suggest that the evolutionary plan for human SULT2A1 lay in the area of general metabolism and detoxification, whereby figure 11.6 Sulfotransferase activity after truncation of the amino- and carboxy-terminal ends of SULT2B1a and SULT2B1b. Wild type WT and constructs of each isoform lacking...

References

Aksoy, I.A., Wood, T.C., and Weinshilboum, R. 1994 . Human liver estrogen sulfotransferase identification by cDNA cloning and expression. Biochem. Biophys. Res. Commun. 200 1621-1629. Bernier, F., Lopez Solache, I., Labrie, F., and Luu-The, V. 1994 . Cloning and expression of cDNA encoding human placental estrogen sulfotransferase. Mol. Cell Endocrinol. 99 R11-R15. Bonham Carter, S.M., Rein, G., Glover, V., Sandler, M., and Caldwell, J. 1983 . Human platelet phenolsulphotransferase M and P...

Aryl Sulfotransferase

Enzyme Property in Sulfo-Conjugation Aryl sulfotransferase activity is found in all mammals De Meio, 1975 . The activity is usually detected in extrahepatic tissues such as brain, small intestine, lung, and blood platelet, although liver shows the highest activity in most substrates. Phenol sulfation is also detected in birds, mollusks, amphibians, insects, and araneids, but not in fishes De Meio, 1975 . In humans, 2-adrenalgic drugs such as salbutamol, terbutaline, and isoprenaline Bonham...

Sult1 Family

The SULT1 family comprises at least 11 proteins segregated into 3 subfamilies Table 1.1 . The SULT1A subfamily members are also known as the phenol SULTs because each of the three 1A isoforms catalyzes the sulfation of phenolic molecules Table 1.3 . HUMAN SULT1A1 has been studied most often within the context of conjugation of phenolic drugs, such as acetaminophen, minoxidil, and 17a-ethinylestradiol. This isoform also sulfates endogenous compounds, such as 17 -estradiol and iodot-hyronines, as...

Classification And Nomenclature Of Sult Genes Identified From Vertebrates

Dendrogram Sult

The number of SULT cDNAs has been isolated not only from animals but also from plants and bacteria in past years, and their primary structures have been identified Marsolais and Varin, 1998 Nagata and Yamazoe, 2000 . In vertebrates, more than 50 sulfotransferases have been isolated and classified into seven gene families from their deduced amino acid homologies in animals so far. These families share less than 40 homology with each other. The SULT1 and SULT2 families, which show catalytic...

Sult4a1 Brain Sults

Expression of the SULTs in brain has been of interest since the identification of high levels of dopamine sulfation in human blood platelets Hart et al., 1979 . This interest level was elevated by the investigation of the role of sulfation in neurosteroid synthesis and activity Baulieu, 1991, 1997 . Both SULT1A1 and SULT1A3 have been identified in human brain tissue Young et al., 1984 and localized to neurons in the central nervous system Zou et al., 1990 . Recently, a novel subfamily of SULTs...

Reversible Sulfation And Hormonal Regulation

Sulfation normally results in a reduction in biological activity relative to the parent molecule, and sulfate conjugates may be excreted from the body or serve as circulating or intracellular stores or as metabolic intermediates from which the free compound can be regenerated by the action of arylsulfatase ARS enzymes Coughtrie et al., 1998 . The ARS enzyme family currently comprises six members Please note, the human SULT, which is named 1C2 in this chapter, corresponds to the human isoform...

Enzymology Of Paps Synthetase

Once inside the cell, inorganic sulfate is transformed into the active sulfate donor PAPS Figure 3.1 . In unicellular organisms and in plants, the two activities involved in sulfate activation are borne by relatively small, separate proteins. In contrast, extensive evidence from mammals suggested that ATP-sulfurylase and APS-kinase constitute a single bifunctional polypeptide i.e., they fractionated together through extensive purification and exhibited common properties and behavior Geller et...

The Importance Of Thyroid Hormone Sulfation During Fetal Development

Type Deiodinaseand Solfate

Thyroid hormone is essential for normal human development, and this is most evident in the central nervous system, where thyroid hormone deficiency in the fetal and neonatal periods can result in severe and prolonged neurodevelopmental deficit. A number of factors are involved in regulating the bioavailability of receptor active thyroid hormone T3 . Of particular importance are the deiodinase and sulfotrans-ferase enzyme systems governing the interconversion and thus activation or deac-tivation...

Nomenclature For Human Sult Alleles And Allozymes

The discovery of nucleotide polymorphisms and haplotypes in human genes is progressing at a rapid pace. This creates considerable difficulties in relation to gene nomenclature, therefore a recommended nomenclature for SULT alleles was also developed. The proposed nomenclature for SULT alleles was based on the work of authors describing nomenclature for allelic variants of other drug metabolizing enzyme genes Daly et al., 1996 Hein et al., 2000 Ingelman-Sundberg et al., 2000 Nebert, 2000 ....

Techniques Used In Sult Research

To further our understanding of the role of sulfation during human development, researchers have studied the expression and relative activities of the major SULT isoforms in human adult and fetal tissues using a variety of biochemical and molecular techniques, which are outlined below. A vital feature of the human SULT enzyme family is the degree of substrate specificity demonstrated by the individual isoforms, and this feature has been exploited in enzyme activity assays. SULT activity can be...

Structure And Function Relationship Of Paps Synthetase

Early studies showed that both the sulfurylase and kinase activities from rat chon-drosarcoma co-purified through gel filtration, ion exchange, and ATP affinity chro-matography, which first suggested that the activities are inseparable Geller et al., 1987 . Subsequently, both activities co-purified through substrate affinity chroma-tography and reversed-phase chromatography, yielding a single band on denaturing polyacrylamide gels. The molecular mass of the native active unit containing both...

Sult1e1 Estrogen Sulfotransferase

Studies on the sulfation of hydroxysteroids and estrogens in human breast cancer cells and endometrial tissues indicated that separate SULT activities were most likely involved. The identification and characterization of these steroid sulfation activities were confused by a lack of consistency in assay conditions and substrate concentrations. Multiple SULTs present in human tissues are capable of conjugating various hydroxysteroid and estrogenic steroids with different affinities. Our...

Gene And Enzyme Designation Of Known Sults

Attendees at the Third International Sulfation Workshop held in Drymen, Scotland, 1996, and the Fourth International ISSX meeting in Seattle, WA, 1995, first agreed that SULT would be adopted as the abbreviation for cytosolic sulfotransferase enzymes, and a symbol was accepted by the HUGO Gene Nomenclature Committee It was agreed that members of the SULT superfamily would be assigned family and subfamily designations on the basis of their amino acid sequence identity. SULTs sharing at least 45...

Molecular Biology And Regulation Paps Synthetase Gene Family

Our earlier cloning of the bifunctional murine sulfurylase-kinase SK1 Li et al., 1995 , which did not allow the identification the underlying etiology of the murine bm phenotype, together with the differential mapping of SK1 to mouse chromosome 3 and the bm mutation to chromosome 19 Kurima et al., 1998 Lane and Dickie, 1968 Rusiniak et al., 1996 led us to consider the possibility that there might be more than one SK gene. A second SK isoform was detected following sequence similarity searching...